The mechanisms of cadmium carcinogenesis are under active investigation. In rats, subcutaneous injection of cadmium induced injection-site tumors in dose-related fashion and testicular tumors that appeared to depend on the extent of chronic degeneration of the testes. Zinc pretreatment reduced cadmium carcinogenesis in a site-specific, route-specific and dose-dependent manner. A clear association of cadmium treatment with neoplastic and hyperplastic foci of the prostate was also recorded. Genetic mechanisms of susceptibility or resistance to cadmium were further explored, and several agents known to hypomethylate DNA were shown to confer tolerance to cadmium cytotoxicity. This resistance correlated with increased synthetic capacity for metallothionein, an inducible protein that confers tolerance to cadmium by high affinity sequestration and a reduction in the methylation of the metallothionein gene. Investigations into the nature of cadmium-binding proteins in target tissues of cadmium carcinogenesis showed an absence of metallothionein in the rat, mouse, and monkey testes and in the rat prostate, while the mouse testes were also shown to contain a highly methylated metallothionein gene when compared to non- target tissue such as liver. These results indicate that the capacity for production of this protein is a key determinant of tissue specificity in cadmium carcinogenesis.